Processes



United States Patent PHENTHIAZINYLALKYL-SULFONATES AND PROCESSES PaulGailliot, Paris, and Jean Robert, Maisons-Lalfitte, :France, assignorstoSociete .des -Usines Chimiques Rhone-Poulenc, Paris, France, a Frenchbody corporate No Drawing. Application'March 15, 1954, SerialNo.'416,418

Claims priority, application Great Britain April 20, 1953 12 Claims.(Cl. 260-243) This invention relates: tophenthiazine derivatives andparticularly to sulphonic .esters of IO-hydroxyalkyl-phen- :thiazinesand processes for'their preparation.

According to the present invention; there areprovided sulphonic estersof the general formula:

where A represents a divalent, straight or branched, saturated,aliphatic hydrocarbon chain containing either 2 or .3 carbon atoms withat least two of said carbon atoms phonic esters of the foregoing generalformula are prepared by reacting an aryl sulphonyl halide ArSOzHal witha -hydroxyalkyl-phenthiazine:

or by reacting a silver saltof an aryl .monosulphonic acid ArSOsAg Witha 10-halogenoalkyl-phenthiazine:

the phenthiazine reactant in each case being either otherwiseunsubstituted. or having in the lor 3-position (Beilstein nomenclature)a substituent in the form ofa halogen atom, (e. g. chlorine), or amethyl or methoxy group. The following examples ,will serve toillustrate the vention:

' Example I To a solution of 1-(10'-phenthia2inyl)-propanol-2 (B. P.0.35 mm. H =190195 C.) (20 g.) in pyridine (60 cc.) there is added asolution of p-toluene sulphonyl chloride (15.45 g.) in pyridine (40 cc.)and the mixture is agitated atroom temperature overnight. The reactionmixture is pouredonto crushed ice (500 g.) and an oily precipitate formswhich crystallises rapidly. Water (500 cc.); is added to complete theprecipitation and themed "uct is filtered ofil washed: with wateranddriedim air. It

is then recrystallised from ethyl acetate (145mm) I 1-(-10-,phenthiazinyl)-propyl-2-p-toluene sulphonate (16. g.) is .thusobtained, which melts at l50151 C. (Kofier).

Example II A solution of silver p-toluene sulphonate (1.45 g.) and 1-(l0-phenthiazinyl)-2-chloropropane 1.4 g.) in acetonitrile (15 cc.) isheated under reflux for 1 /2 hours. The reaction mixture is allowed tocool and the silver chloride precipitated is filtered off. The filtrateis concentrated under vacuum and is then taken up in chloroform(l5.cc.). The insoluble material (silver chloride) is filtered OE andthe filtrate concentrated under vacuum. The solid residue obtained istaken up in ethyl acetate (8 cc.) and the insoluble material is filteredoff and washed with ethyl acetate (2 cc.). There is thus obtained1-(10'-phenthiazinyl) propyl-Z-p-toluene sulphonate (1.35 g.), whichafter recrystallisation from ethyl acetate melts at 149l51 C. (Kofler).

Example 111 A solution of silver p-toluene sulphonate (1.67 g.) and1-(10'-phenthiaziny1)-2-chloroethane 1.5 g.) in dimethylformamide (10cc.) is heated under reflux for 2 /2 hours.

The reaction mixture is allowed to cool; the silver chlorideprecipitated is filtered off and washed with dimethylformamide (2 cc.).On pouring the filtrate into water (50 cc.) a thick oil is precipitatedwhich is extracted with ether (50 cc., then twice with 25 cc.). Thecombined ether extracts are washed with Water (25 cc.) and dried oversodium sulphate. On driving oif, under vacuum, some of the ether, theproduct crystallises. The product is filtered off and washed with ether(5 cc.). There is thus ob tained l-(l0'-phenthiazinyl)ethyl-Z-p-toluenesulphonate (0.9 g.) which, after recrystallisation from ethyl acetate,melts at 141 C. (Kofler).

Example IV Benzene sulphonyl chloride (6.4 g.) is added to a solution of1-(3'-chloro-10'-phenthiazinyl)propan-3-ol (10 g.) in pyridine (20 cc.).The reaction mixture is stirred for 5 hours, left overnight at roomtemperature and then poured into Water (200 cc.). The product isprecipitated as an orange oil which will not crystallise. Afterneutralisation with hydrochloric acid (19 cc., density 1.19), theproduct is extracted with chloroform cc., 30 cc. and then 20 cc.). Thecombined chloroform extracts are washed with 2 N hydrochloric acid (30cc.) and then with water (50 cc.). After drying the chloroform extractsover sodium sulphate, the chloroform is driven off under vacuum byheating on a water-bath. There is thus obtained an orange-red veryviscous oil which is l-(3-chloro-l0-phenthiazinyl)propyl-3-benzenesulphonate (12.5 g.).

The identity of the compound is demonstrated by its analysis and byreaction with diethylamine which gives 1- (3 '-chloro-10'-phenthiazinyl)-3-diethylamino-propane, the hydrochloride of which melts at 178 C.(Kofier).

Example V p-Toluene sulphonyl chloride (7.05 g.) is added to a solutionof 1-(3-methyl-10-phenthiazinyl)propan-B-ol (10 g.) in pyridine (50cc.). The reaction mixture is stirred for 3 hours, left overnight atroom temperature and then poured into a mixture of ice (250 g.), water(250 cc.) and hydrochloric' acid (50'cc., density 1.19). 'An.oil isprecipitated, which is extracted withdieth'yl ether (two times 200 cc.).The ether solutions are combined, washed with 50 cc. of a saturatedsolution of sodium bicarbonate and then with 50 cc. of water. After.drying the ether solution over sodium sulphate, the ether is driven oil?by heating on a water-bath. There is thus obtained 1-(3'- methyl-10phenthiazinyl)propyl-3-p-toluene sulphonate (8.5 g.).

The identity of the compound is demonstrated by its analysis and byreaction with diethylamine which gives 1-(3-methyl-l0-phenthiazinyl)-3-diethylamino-propane, the hydrochloride ofwhich melts at 166 168 C. i The sulphonic esters of the presentinvention are of especial value as intermediates in the preparation ofcompounds of therapeutic activity. Thus, they may be reacted withprimary or secondary amines to yield compounds of outstandingpharmacological activity, e. g. the product 1 (3'chloro-l'-phenthiazinyl)-3-diethylaminopropane referred to at the end ofExample 1V above. The use of the sulphonic esters of the presentinvention in the production of compounds of therapeutic value isdescribed in co-pending application Ser. No. 422,698.

We claim:

1. A compound selected from the class consisting of sulphonic esters ofthe general formula:

3. 1-(10' phenthiazinyl)ethyl-Z-p-toluene sulphonate having the formula:

4. 1-(3-chloro-10-phenthiaziny1)propyl-3-benzene sulfonate having theformula:

rim-cm-om-m-msQ 5. 1-(3-methyl phenthiazinyl) propyl-S-p-toluenesulphonate having the formula:

fJH CH -CIEh-O-OgS-Q-CH;

6. A process for the production of a compound selected from the classconsisting of sulphonic esters of the general formula:

where A represents a divalent saturated aliphatic hydrocarbon groupingcontaining from 2 to 3 carbon atoms, at least 2 carbon atoms of saidgrouping being linked as a chain between the ring nitrogen atom and theadjacent oxygen atom of the said formula, Ar represents an aromaticwholly hydrocarbon monocyclic radical and corresponding compoundscontaining in one only of the 1- and 3-positions a group selected fromthe class consisting of halogen, methyl and methoxy groups, whichcomprises reacting an aryl sulphonyl halide of the formula ArSOzHal witha 10-hydroxyalkylphenthiazine selected from compounds of the formula:

and corresponding compounds containing in one only of the 1- and3-positions a group selected from the class consisting of halogen,methyl and methoxy groups.

7. A process for the production of a compound selected from the classconsisting of sulphonic esters of the general formula:

where A represents a divalent, saturated aliphatic hydrocarbon groupingcontaining from 2 to 3 carbon atoms, at least 2 carbon atoms of saidgrouping being linked as a chain between the ring nitrogen atom and theadjacent oxygen atom of the said formula, Ar represents an arcmaticwholly hydrocarbon monocyclic radical and corresponding compoundscontaining in one only of the 1- and 3-positions a group selected fromthe class consisting of halogen, methyl and methoxy groups, whichcomprises reacting a silver salt of an aryl sulphonic acid of theformula ArSOzAg with a 10-halogenoalkyl-phenthiazine selected fromcompounds of the formula:

which comprises reacting 1-(10'-phenthiazinyl)-propanol- 2 withp-toluene sulphonyl chloride, in the presence of an acid-binding agent.

9. A process for the production of1-(10'-phenthiazinyl)propyl-2-p-to1uene sulphonate having the formula:

which comprises reacting 1-(10'-phenthiazinyl)2-chloropropane withsilver p-toluene sulphonate.

10. A process for the production of l-('-phenthiazinyl)ethyl-2-p-toluenesulphonate having the formula:

which comprises reacting 1-(10-phenthiazinyl)-2-chloroethane with silverp-toluene sulphonate.

11. A process for the production of 1-(3'-chloro-10-phenthiazinyl)-propy1-3-benzene sulphonate having the formula:

which comprises reacting l-(3'-chloro-10-phenthiazinyl) propan-B-ol withbenzene sulphonyl chloride in the presence of an acid-binding agent 12.A process for the production of 1-(3-methyl-10-phenthiazinyl)-propyl-3-p-toluene sulphonate. having the formula:

N CH;

which comprises reacting 1-(EV-methyl-10'-phenthiazinyl) propan-3-o1with p-toluene sulphonyl chloride in the presence of an acid-bindingagent.

References Cited in the file of this patent

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF SULPHONIC ESTERS OFTHE GENERAL FORMULA:
 6. A PROCESS FOR THE PRODUCTION OF A COMPOUNDSELECTED FROMTHE CLASS CONSISTING OF SULPHONIC ESTERS OF THE GENERALFORMULA:
 7. A PROCESS FOR THE PRODUCTION OF A COMPOUND SELECTED FROM THECLASS CONSISTING OF SULPHONIC ESTERS OF THE GENERAL FORMULA: